Glycopeptides

Mark Johnson, Pharm.D., BCPS Associate Professor and Director of Postgraduate Education

Vancomycin—A glycopeptide

http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1399

Vancomycin

• • Mechanism of action – Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of of peptidoglycan pentapeptide, which as a result inhibits transglycosylase, preventing peptidoglycan elongation and cross-linking Mechanism of Resistance: modification of D-Ala-D Ala binding site (D-Ala is replaced by D-lactate), and thus vancomycin cannot bind to its target site

Vancomycin

• Spectrum of Activity – Gram + organisms only (Staph and Strep); particularly Staphylococci (MRSA), penicillin-resistant Streptococcus pneumoniae – Synergistic in vitro with gentamicin and streptomycin against Enterococcus faecium and Enterococcus faecalis – Increased incidence of VRE, but otherwise good coverage against enterococcus – Vancomycin Resistance: VISA (GISA), VRSA – Kills Staph slowly compared to beta-lactams – Bacteriocidal

Vancomycin

• Clinical Use – PO for C. difficile colitis – IV for everything else (usually serious infections including bacteremia, endocarditis, meningitis) – Also an alternative for PCN allergic patients

Vancomycin

• Pharmacokinetics – Poorly absorbed from GI tract – Widely distributed with Vd 0.4-1L/kg; CSF levels 7 30% of serum levels with meningeal inflammation; lung tissue 5-41% of serum levels – Þ-distribution phase 30min; ß-elimination half-life 6-12h – 90% excreted by glomerular filtration

Vancomycin

• Adverse Effects: – Nephrotoxicity (uncommon, but ? Increasing incidence) and Ototoxicity (rare--possibly related to very high trough conc) • More common with older preparation (“Mississippi mud”) • Toxicity may be increased with other nephro/oto-toxic drugs

Vancomycin

• Adverse Effects: – “Red man” or “red neck” syndrome • Infusion-related flushing reaction caused by release of histamine • Prevented by increasing the infusion time – Phlebitis – Rash – Chills – Fever

Vancomycin

• Dosing – 15-20mg/kg (as actual body weight) every 8 12h for most patients with normal renal function when MIC < 1 – Dose modify interval depending on renal impairment – In seriously ill, LD 25-30mg/kg can be used to facilitate rapid attainment of target trough – Goal AUC:MIC >400 overall; not achievable if MIC > 2 with conventional dosing AJHP 2009;66:82-98

Vancomycin

• Monitoring: – Troughs most accurate and practical for monitoring efficacy – Trough historically 5-10mcg/ml, now >10mcg/mL because of MIC creep – Complicated infections (endocarditis, osteomyelitis, meningitis, HAP caused by Staph aureus): trough 15-20mg/L – Scr periodically AJHP 2009;66:82-98

Vancomycin

• Dosage Forms: – Capsules (Vancocin®) 125mg and 250mg – Injection • Premixed: 500mg (100ml); 1g (200ml) • Powder for reconstitution: 500mg, 1gm, 5gm, 10gm

Telavancin (Vibativ™) Theravance

• • Lipoglycopeptide antibiotic (synthetic derivative of vancomycin) for the treatment of complicated gram-positive skin infections MOA: inhibits bacterial cell wall synthesis and disrupts bacterial cell membrane function

Televancin vs. Vancomycin

Telavancin (Vibativ™) Theravance

• • Antimicrobial Activity: – MSSA, MRSA – Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae (incl. penicillin resistant), Streptococcus angiosus group – Enterococcus faecalis – – Not VRE, not VRSA, maybe GISA PAE of up to 6 hours Efficacy: – Skin and Skin Structure: comparable to vancomycin and anti-staphylococcal penicillins – HAP: comparable to vancomycin

• •

Telavancin (Vibativ™) Theravance

ADR’s: – >10%: taste disturbance, n&v, foamy urine – Renal dysfunction: 3% (vs. 1% vancomycin) (monitor renal function before/during therapy) – Possible: QTc prolongation, Red-man syndrome – Pregnancy C: reduced fetal weights, digit/limb deformities in animals (need to do pregnancy test) Drug Interactions: – Is a CYP3A4 inhibitor, so potential exists – Can interfere with PT, INR, aPTT, ACT, factor Xa as binds to artificial phospholipid surface—collect samples when telavancin is at trough

Telavancin (Vibativ™) Theravance

• • Dosing: – 10mg/kg Q24h IV over 60min • • CrCl 30-50ml/min: 7.5mg/kg Q24h CrCl 10-29ml/min: 10mg/kg Q48h • • CrCl < 10ml/min: insufficient data Severe hepatic impairment: unknown – No level monitoring Cost: – – 750mg vial: $150 250mg vial: $50